Metabolic diseases such as type 2 diabetes (T2D), obesity and their related co-morbidities have reached epidemic proportions worldwide. While progress continues to be made into the molecular mechanisms involved in both obesity and T2D, the identification and development of safe, efficacious therapeutic modalities is significantly limited. There is an urgent need for innovative medicines to combat both obesity and diabetes. Recent data along with our Phase 1 data strongly suggest that pharmacological intervention of Fyn kinase provides an excellent target and novel approach for the discovery of new drugs to treat metabolic disease. We have identified a promising selective Fyn kinase inhibitor and completed initial SAR to generate a novel and selective lead compound. This proposal describes an integrated approach for further development and optimization of our lead compound through medicinal chemistry, in vitro characterization and functional cell-based activity. The most effective compounds advancing through the optimization paradigm will be used to validate this approach in animal models of type 2 diabetes.